摘要
第一部分:GABA能神经传递紊乱与抑郁症患者HPA轴过度激活的关系
目的:下丘脑室旁核(hypothalamic paraventricular nucleus, PVN)中的促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)神经元的激活在情感障碍发病机制中扮演着至关重要的作用。γ-氨基丁酸(Gamma-aminobutyric acid, GABA)是主要的抑制性神经递质之一。我们的假说是抑郁症中下丘脑PVN中GABA能神经递质失调可能会导致CRH免疫反应性(immunoreactive, IR)神经元的过度激活。方法:通过免疫细胞化学和图像分析方法对14位情感障碍患者和12位对照者下丘脑PVN中的谷氨酸脱羧酶(Glutamic acid decarboxylase, GAD65/67)免疫染色进行定量分析。14位情感障碍患者中9位患有重性抑郁(major depressive disorder, MDD),5位患有双向障碍(bipolar disorder, BD)。此外,我们还对这些个体的下丘脑PVN中CRH-IR神经元总数进行了分析。
结果:情感障碍患者PVN-GAD65/67呈现神经末梢点状染色分布。GAD65/67-IR结构的密度比对照组低(P=0.080),在MDD组降低更为显著(P=0.028),PVN-GAD65/67-IR表达的下降伴随着PVN-CRH-IR神经元总数的显著增加。在情感障碍组中,PVN-GAD65/67-IR结构的密度与CRH-IR神经元总数之间存在显著负相关(rho=-0.527,P=0.032,n=13),该显著相关性在对照组中不存在。
结论:情感障碍患者(尤其是MDD)PVN中GABA能神经支配减弱,降低了GABA对CRH-IR神经元的抑制作用,这是抑郁症患者HPA轴活性亢进的重要机制之一。
第二部分:NOS-NO系统在应激动物模型中的初步研究
目的:已有研究表明,气体性神经递质一氧化氮(nitric oxide, NO)及其神经元型NO合酶(neuronal NO synthase, nNOS)在抑郁症患者大脑和血浆中发生明显改变,但是它们参与抑郁症发病的作用机制尚不清楚。本文旨在探讨NOS-NO系统在应激后大鼠下丘脑和血浆中是否改变,从而为将来研究NOS-NO系统参与抑郁症发病机制寻找恰当的动物模型和提供科学依据。
方法:在成年雄性大鼠建立足底电击诱导的急性应激模型和慢性不可预知性应激(chronic unpredicted stress, CUS)模型。对照组未受到任何刺激。CUS大鼠先进行旷场实验和糖水偏好实验后取材。血浆中NO代谢物(硝酸盐和亚硝酸盐,NOx)、皮质酮(CORT)以及下丘脑NOS活性分别通过各自的商业化试剂盒进行测定。在下丘脑室旁核(paraventricular nucleus, PVN)中进行CRH和nNOS免疫细胞化学研究,应用图像分析软件进行定量分析。nNOS与CRH、血管加压素、催产素等神经肽在PVN的共定位关系通过免疫荧光双标实验观察。
结果:血浆中CORT水平在足底电击0、5、15和30min后显著升高(P≤0.038),血浆中NOx水平分别在0和30min出现高峰(P≤0.005)。下丘脑PVN中CRH-IR于足底电击后15min(P=0.024)和30min(P=0.022)明显增强,而nNOS-IR于足底电击后15min明显减弱(P=0.030)。下丘脑总NOS活性在足底电击后15min明显下降(P=0.028)。CUS大鼠在旷场和糖水偏好实验中表现出抑郁焦虑样行为,血浆中CORT(P=0.001)和NOx(P=0.001)水平均显著升高,下丘脑总NOS活性在CUS后明显下降(P=0.025),下丘脑PVN中nNOS阳性细胞密度在CUS组中显著下降(P=0.019),并且该显著性降低在nNOS强阳性细胞和nNOS弱阳性细胞上均有所体现。nNOS-IR主要与催产素神经元共存,而几乎不表达于CRH-IR神经元。
结论:在足底电击诱导的急性应激反应和CUS诱导的抑郁症动物模型中,下丘脑总NOS的活性和PVN-nNOS表达显著降低,血浆NO水平却明显升高。此外,足底电击后nNOS-IR并不与CRH-IR神经元共存,而是主要表达在催产素细胞上。因此,nNOS与催产素神经元的相互作用将是研究nNOS参与应激反应机制的重要线索之一。
第三部分:NOS-NO系统通过改变GABA能神经传递参与抑郁症患者前额叶皮层功能调节
目的:前额叶皮层(prefrontal cortex, PFC)在结构和功能上的异常与抑郁症的病因学和症状学密切相关。近年来研究表明,气体性神经递质一氧化氮(nitric oxide, NO)在抑郁症病理过程中发挥重要作用,但是它是否参与并如何调节PFC的活性目前还不清楚。因此,本文旨在研究抑郁症患者脑脊液(cerebrospinal fluid, CSF)中NO含量和PFC中NO合酶(NO synthase),即神经型NOS (neuronal NOS)、内皮型NOS (endothelial NOS)和诱导型NOS (iNOS)的表达。此外,我们还研究了选择性阻断nNOS来源的NO产生对PFC-GABA能神经元活性的影响。方法:通过测定CSF内NO代谢产物,即硝酸盐和亚硝酸盐(NO、)的含量来反映抑郁症患者和匹配的对照者CSF中NO水平。采用实时定量PCR技术检测背外侧PFC (dorsolateral PFC, DLPFC)和前扣带回皮层(anterior cingulate cortex, ACC)中的nNOS.eNOS和iNOS的mRNA水平。应用免疫细胞化学方法和图像分析软件在ACC中定量分析nNOS蛋白水平,并通过免疫荧光双标技术观察nNOS与谷氨酸脱羧酶(GAD65/67)的共定位情况。此外,应用nNOS的选择性抑制剂7-nitroindazole(7一NI)处理小鼠ACC脑片,观察其对GABA能神经元电生理活动的改变。
结果:抑郁症组CSF-NOx水平显著低于对照组(P=0.007)。抑郁症患者ACC中,而不是DLPFC中,nNOS-mRNA水平具有降低的趋势(P=0.083).nNOS-IR王要分布在正常人脑ACC的Ⅱ/Ⅲ层。在抑郁症患者组中,ACC-nNOS-IR在整个灰质中的细胞密度和平均光密度均降低(P=0.083),尤其是ACC的Ⅱ/Ⅲ层降低更为显著(P=0.043)。对照组nNOS-IR在ACC灰质中的细胞密度与CSF-NOx水平呈显著正相关(rho=0.667,P=0.050,n=9).nNOS与GABA能神经元的标记物GAD65/67在抑郁症患者ACC中存在明显共定位。此外,nNOS选择性抑制剂7-NI与ACC脑片孵育显著增加了GABA介导的抑制性突触后电流(mIPSCs)的频率(P<0.05, n=11),但未改变mIPSCs的幅度。
结论:抑郁症患者ACC-nNOS表达下调,CSF-NOx水平减低,选择性抑制小鼠ACC中的nNOS活性显著影响了GABA能神经传递。
Part Ⅰ:Dysregulation of GABAergic neurotransmission and the hyperactivated HPA axis in depression
Objectives:Activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) is crucial in the pathogenesis of mood disorder. Gamma-aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters. We hypothesized that dysregulation of GABAergic neurotransmission contributes to the hyperactivity of CRH-immunoreactive (IR) neurons in depression.
Methods:Glutamic acid decarboxylase (GAD)65/67-IR boutons were quantified in the postmortem PVN by image analysis in14mood disorder patients (9major depressive disorder, MDD,5bipolar disorder, BD) and12controls. For some of these subjects the total number of CRH-IR neurons in the PVN was also analyzed.
Results:The density of GAD65/67-positive structures decreased in mood disorder patients (P=0.080), especially in MDD group (P=0.028), compared to the matched controls. The reduction in GAD65/67-IR was accompanied by significantly increased numbers of CRH-IR neurons. In addition, a negative correlation between PVN-GAD65/67-IR density and CRH-IR neuron numbers was found in the mood disorder group (rho=-0.527, P=0.032, n=13), but not in the control group.
Conclusions:A diminished GABAergic input to the PVN may contribute to the activation of CRH-IR neurons in depression, most prominently in MDD. This is an important factor that leads to the overeactivity of HPA axis in depression.
Part Ⅱ:A preliminary study on the alteration of NOS-NO system in stress animal models
Objective: The gaseous neurotransmitter nitric oxide (NO) and neuronal NO synthase (nNOS) were reported to be altered in the brain and plasma in depression, but the underlying mechanism remains unknown. Therefore, we investigated in stress models the changes of NOS-NO pathway in the rat hypothalamus and plasma so as to search for an ideal model and provide scientific evidence for future research.
Methods:Adult male rats were used to establish chronic unpredicted stress (CUS) model and acute stress model induced by foot shock, none of any stimuli was subjected to control rats. Open field test and sucrose preference test were performed on CUS rats. Plasma NO metabolites, plasma corticosterone (CORT) levels, and hypothalamic NOS activity were determined by respective commercial kits. The density of CRH-and nNOS-expressing cells was quantified in the hypothalamic paraventricular nucleus (PVN) by image analysis. Co-localization between nNOS and the neuropeptides, i.e. CRH, vasopressin and oxytocin in the PVN was observed by double immunofluorescence.
Results:Significant increases of plasma CORT were observed after foot shock at0,5,15and30min (P<0.038), and for levels of NO metabolites at0and30min (P<0.005). The density of CRH-immunoreactivity (IR) increased at15min (P=0.024) and30min (P=0.022), while nNOS-IR deceased at15min (P=0.030) in the hypothalamic PVN after foot shock. The total NOS activity decreased at15min in the hypothalamus after foot shock (P=0.028). CUS rats showed depression-and anxiety-like behaviors in open field test and sucrose preference test. CUS rats had higher CORT (P=0.001) and NOX (P=0.001) levels in plasma than control rats. In the CUS model, nNOS-IR cell density significantly decreased in the hypothalamic PVN (P=0.019), and this reduction was based upon both strongly and weakly stained neurons. The total NOS activity significantly decreased in the hypothalamus of CUS rats (P=0.025). nNOS-IR was mainly expressed in oxytocin-positive neurons, but hardly colocalized with CRH-IR neurons.
Conclusion:The present study showed a decrease of cNOS activity and PVN-nNOS expression in the hypothalamus, but an increase of NO levels in plasma both in foot shock-induced acute stress and CUS-caused depression models. In addition, nNOS did not express in CRH-IR neurons, but in oxytocin-IR neurons after foot shock. The interaction between nNOS and oxytocin will thus be a promising clue to reveal the role of nNOS in stress responses.
Part Ⅲ:NOS-NO system is involved in the regulation of prefrontal cortex function by affecting GABAergic neurotransmission in depression
Objective: Alterations in prefrontal cortex (PFC) are crucially involved in the etiology and symptoms of depression. A key role of the gaseous neurotransmitter nitric oxide (NO) has also been proposed, but whether and how NO affect the PFC activity are largely unknown in depression. The present study, therefore, aimed to determine the putative changes of brain NO production, and the transcriptional and/or protein level of the isoforms of the NO synthase (NOS), i.e. neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS) in the PFC in depression. Meanwhile, we investigated the effects of NO on GABAergic neuronal activity by selectively blocking the nNOS activity.
Methods:The levels of NO, as determined by its metabolites nitrate and nitrite (NOx), were measured in the postmortem ventricular cerebrospinal fluid (CSF) of depressed patients and matched controls. The mRNA levels of nNOS, eNOS and iNOS were measured by real-time PCR in the dorsolateral PFC (DLPFC) and in the anterior cingulate cortex (ACC) of depressed patients. ACC-nNOS immunoreactivity (IR) was assessed by immunocytochemistry and image analysis, and the colocalization between nNOS and GAD65/67was observed by double immunofluorescence. Moreover,7-nitroindazole, the selective nNOS inhibitor, was applied to ACC slices and observed the effects of nNOS-derived NO on the electrophysiological activity GABAergic neurons.
Results:We found a significant decrease of CSF-NOx levels in the depressed patients compared to controls (P=0.007). There was a trend toward a lower nNOS mRNA levels in depression in ACC (P=0.083), but not in DLPFC (P=0.939). nNOS-IR was observed to be mainly distributed in the layer Ⅱ/Ⅲ of the human ACC, and a remarkable decrease of nNOS-IR in the grey matter of ACC (P=0.083), especially in layer II/III (P=0.043), was found in depressed patients. A significant positive correlation between the CSF-NOx levels and the ACC-nNOS-IR cell numbers was found in the control group (rho=0.667, P=0.050, n=9). Co-localization between nNOS and GAD65/67, the marker of GABAergic neurons, was found in the human ACC. Furthermore, bath application of7-NI in ACC slices significantly enhanced the frequency of GABAergic mIPSCs (P<0.05; n=11), but did not significantly alter mIPSC amplitude.
Conclusion:A diminished ACC-nNOS expression and a decreased CSF-NOX level were found in depression. Selectively inhibiting nNOS activity had a significant effect on GABAergic neurotransmission in mouse ACC slices.
引文
Banki CM, Karmacsi, L, Bissette, G, and Nemeroff, CB.1992. CSF corticotropin-releasing hormone and somatostatin in major depression:response to antidepressant treatment and relapse. Eur Neuropsychopharmacol 2:107-13.
Bao AM, Hestiantoro, A, Van Someren, EJ, Swaab, DF, and Zhou, JN.2005. Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in mood disorders. Brain 128:1301-13.
Bao AM, Meynen, G, and Swaab, DF.2008. The stress system in depression and neurodegeneration: Focus on the human hypothalamus. Brain Res Rev 57:531-53.
Bao AM, and Swaab, DF.2007. Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic paraventricular nucleus and the role of sex hormones. Neuroendocrinology 85:27-36.
Bartanusz V, Muller, D, Gaillard, RC, Streit, P, Vutskits, L, and Kiss, JZ.2004. Local gamma-aminobutyric acid and glutamate circuit control of hypophyseotrophic corticotropin-releasing factor neuron activity in the paraventricular nucleus of the hypothalamus. Eur JNeurosci 19:777-82.
Belmaker RH.2008. The future of depression psychopharmacology. CNS Spectr 13:682-7.
Benes FM, Todtenkopf, MS, Logiotatos, P, and Williams, M.2000. Glutamate decarboxylase (65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. J Chem Neuroanat 20:259-69.
Bernstein H-G, Dobrowolny, H, and Bogerts, B.2007. Disturbed cross-talk between hypothalamic neuropeptides, nitric oxide and other factors may significantly contribute to the hyperactivity of the HPA axis in depression and schizophrenia. In BA Levine, ed., Neuropeptide Research Trends. Nova Publishers.
Bossers K, Meerhoff G, Balesar R, et al.2009. Analysis of gene expression in Parkinson's disease:possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 19(1):91-107.
Boudaba C, Szabo, K, and Tasker, JG.1996. Physiological mapping of local inhibitory inputs to the hypothalamic paraventricular nucleus. JNeurosci 16:7151-60.
Bowers G, Cullinan, WE, and Herman, JP.1998. Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits. J Neurosci 18:5938-47.
Brambilla P, Perez, J, Barale, F, Schettini, G, and Soares, JC.2003. GABAergic dysfunction in mood disorders. Mol Psychiatry 8:721-37,715.
Carpenter LL, Schecter, JM, Tyrka, AR, Mello, AF, Mello, MF, Haggarty, R, et al.2006. Open-label tiagabine monotherapy for major depressive disorder with anxiety. J Clin Psychiatry 67:66-71.
Dallman MF, Pecoraro, NC, La Fleur, SE, Warne, JP, Ginsberg, AB, Akana, SF, et al.2006. Glucocorticoids, chronic stress, and obesity. Prog Brain Res 153:75-105.
Decavel C, and Van den Pol, AN.1990. GAB A:a dominant neurotransmitter in the hypothalamus. J ComP Neurol 302:1019-37.
Decavel C, and van den Pol, AN.1992. Converging GAB A-and glutamate-immunoreactive axons make synaptic contact with identified hypothalamic neurosecretory neurons. J Comp Neurol 316:104-16.
Dracheva S, Elhakem, SL, McGurk, SR, Davis, KL, and Haroutunian, V.2004. GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. J Neurosci Res 76:581-92.
Fatemi SH, Stary, JM, Earle, JA, Araghi-Niknam, M, and Eagan, E.2005. GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr Res 72:109-22.
Fronczek R, Overeem S, Lee SY, et al.2007. Hypocretin (orexin) loss in Parkinson's disease. Brain 130(Pt6):1577-85.
Gao SF, and Bao, AM.2011. Corticotropin-Releasing Hormone, Glutamate, and {gamma}-Aminobutyric Acid in Depression. Neuroscientist 17:124-44.
Goncharuk VD, Van Heerikhuize, J, Swaab, DF, and Buijs, RM.2002. Paraventricular nucleus of the human hypothalamus in primary hypertension:activation of corticotropin-releasing hormone neurons. J Comp Neurol 443:321-31.
Goren MZ, Kucukibrahimoglu, E, Berkman, K, and Terzioglu, B.2007. Fluoxetine partly exerts its actions through GABA:a neurochemical evidence. Neurochem Res 32:1559-65.
Guidotti A, Auta, J, Davis, JM, Di-Giorgi-Gerevini, V, Dwivedi, Y, Grayson, DR, et al.2000. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57:1061-9.
Heckers S, Stone, D, Walsh, J, Shick, J, Koul, P, and Benes, FM.2002. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry 59:521-9.
Heim C, Newport, DJ, Mletzko, T, Miller, AH, and Nemeroff, CB.2008. The link between childhood trauma and depression:insights from HPA axis studies in humans. Psychoneuroendocrinology 33:693-710.
Herman JP, Mueller, NK, and Figueiredo, H.2004. Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci 1018:35-45.
Huitinga I, Erkut, ZA, van Beurden, D, and Swaab, DF.2004. Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions. Ann Neurol 55:37-45.
Jones MT, Gillham, B, Altaher, AR, Nicholson, SA, Campbell, EA, Watts, SM, et al.1984. Clinical and experimental studies on the role of GAB A in the regulation of ACTH secretion:a review. Psychoneuroendocrinology 9:107-23.
Kling MA, Geracioti, TD, Licinio, J, Michelson, D, Oldfield, EH, and Gold, PW.1994. Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression:preliminary findings. Psychopharmacol Bull 30:489-94.
Kovacs KJ, Miklos, IH, and Bali, B.2004. GABAergic mechanisms constraining the activity of the hypothalamo-pituitary-adrenocortical axis. Ann N Y Acad Sci 1018:466-76.
Kucukibrahimoglu E, Saygin, MZ, Caliskan, M, Kaplan, OK, Unsal, C, and Goren, MZ.2009. The change in plasma GABA, glutamine and glutamate levels in fluoxetine-or S-citalopram-treated female patients with major depression. Eur J Clin Pharmacol 65:571-7.
Meier J, and Grantyn, R.2004. A gephyrin-related mechanism restraining glycine receptor anchoring at GABAergic synapses. JNeurosci 24:1398-405.
Nemeroff CB, Bissette, G, Akil, H, and Fink, M.1991. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin. Br J Psychiatry 158:59-63.
Nemeroff CB, Widerlov, E, Bissette, G, Walleus, H, Karlsson, I, Eklund, K, et al.1984. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226:1342-4.
Nikisch G, and Mathe, AA.2008. CSF monoamine metabolites and neuropeptides in depressed patients before and after electroconvulsive therapy. Eur Psychiatry 23:356-9.
Perry EK, Gibson, PH, Blessed, G, Perry, RH, and Tomlinson, BE.1977. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 34:247-65.
Petroff OA.2002. GABA and glutamate in the human brain. Neuroscientist 8:562-73.
Purba JS, Hoogendijk, WJ, Hofman, MA, and Swaab, DF.1996. Increased number of vasopressin-and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 53:137-43.
Raadsheer FC, Hoogendijk, WJ, Stam, FC, Tilders, FJ, and Swaab, DF.1994. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60:436-44.
Raadsheer FC, van Heerikhuize, JJ, Lucassen, PJ, Hoogendijk, WJ, Tilders, FJ, and Swaab, DF.1995. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiatry 152:1372-6.
Roy A, Pickar, D, Paul, S, Doran, A, Chrousos, GP, and Gold, PW.1987. CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 144:641-5.
Sanacora G, and Saricicek, A.2007. GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS Neurol Disord Drug Targets 6:127-40.
Swaab DF, Bao, AM, and Lucassen, PJ.2005. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4:141-94.
Verkuyl JM, Hemby, SE, and Joels, M.2004. Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. Eur J Neurosci 20:1665-73.
Verwer RW, and Raber-Durlacher, JE.1993. Efficient and unbiased estimation of volume and area of tissue components and cell number in gingival biopsies. J Periodontal Res 28:313-23.
Widerlov E.1988. A critical appraisal of CSF monoamine metabolite studies in schizophrenia. Ann N YAcad Sci 537:309-23.
Yamada MK, Nakanishi, K, Ohba, S, Nakamura, T, Ikegaya, Y, Nishiyama, N, et al.2002. Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J Neurosci 22:7580-5.
Arborelius L, Owens MJ, Plotsky PM, et al.1999. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160(1):1-12.
Bao AM, Meynen G, Swaab DF.2008. The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 57(2): 531-53.
Bernstein HG, Heinemann A, Krell D, et al.2005. Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleus. Cell Mol Biol (Noisy-le-grand) 51(3):279-84.
Bernstein HG, Heinemann A, Krell D, et al.2002. Further immunohistochemical evidence for impaired NO signaling in the hypothalamus of depressed patients. Ann N Y Acad Sci 973:91-3.
Bernstein HG, Jirikowski GF, Heinemann A, et al.2000. Low and infrequent expression of nitric oxide synthase/NADPH-diaphorase in neurons of the human supraoptic nucleus:a histochemical study. J Chem Neuroanat 20(2):177-83.
Bernstein HG, Stanarius A, Baumann B, et al.1998. Nitric oxide synthase-containing neurons in the human hypothalamus:reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience 83(3):867-75.
Bredt DS, Snyder SH.1989. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A 86(22):9030-3.
Chen XN, Meng QY, Bao AM, et al.2009. The involvement of retinoic acid receptor-alpha in corticotropin-releasing hormone gene expression and affective disorders. Biol Psychiatry 66(9):832-9.
Costa A, Trainer P, Besser M, et al.1993. Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro. Brain Res 605(2):187-92.
Dagyte G, Van der Zee EA, Postema F, et al.2009. Chronic but not acute foot-shock stress leads to temporary suppression of cell proliferation in rat hippocampus. Neuroscience 162(4):904-13.
Edwards TM, Rickard NS.2007. New perspectives on the mechanisms through which nitric oxide may affect learning and memory processes. Neurosci Biobehav Rev 31(3):413-25.
Fagan KA, Tyler RC, Sato K, et al.1999. Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation. Am J Physiol 277(3 Pt 1):L472-8.
Gao SF, Bao AM.2011. Corticotropin-releasing hormone, glutamate, and gamma-aminobutyric acid in depression. Neuroscientist 17(1):124-44.
Griffith OW, Stuehr DJ.1995. Nitric oxide synthases:properties and catalytic mechanism. Annu Rev Physiol 57:707-36.
Grippo AJ, Johnson AK.2009. Stress, depression and cardiovascular dysregulation:a review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress 12(1):1-21.
Harkin A, Houlihan DD, Kelly JP.2002. Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine. J Psychopharmacol 16(2):115-23.
Helmreich DL, Parfitt DB, Walton JR, et al.2008. Dexamethasone and stressor-magnitude regulation of stress-induced transcription of HPA axis secretagogues in the rat. Stress 11(4):302-11.
Jimenez-Ortega V, Cardinali DP, Poliandri AH, et al.2007.24-Hour rhythm in gene expression of nitric oxide synthase and heme-peroxidase in anterior pituitary of ethanol-fed rats. Neurosci Lett 425(2):69-72.
Karolewicz B, Szebeni K, Stockmeier CA, et al.2004. Low nNOS protein in the locus coeruleus in major depression. J Neurochem 91(5):1057-66.
Kim YK, Paik JW, Lee SW, et al.2006. Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1091-6.
Lee BH, Lee SW, Yoon D, et al.2006. Increased plasma nitric oxide metabolites in suicide attempters. Neuropsychobiology 53(3):127-32.
McLeod TM, Lopez-Figueroa AL, Lopez-Figueroa MO.2001. Nitric oxide, stress, and depression. Psychopharmacol Bull 35(1):24-41.
Oliveira RM, Guimaraes FS, Deakin JF.2008. Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. Braz J Med Biol Res 41(4):333-41.
Palumbo ML, Fosser NS, Rios H, et al.2007. Loss of hippocampal neuronal nitric oxide synthase contributes to the stress-related deficit in learning and memory. J Neurochem 102(1):261-74.
Paxinos G, Watson C,1986. The Rat Brain in Stereotaxic Coordinates. Academic Press, New York.
Raadsheer FC, Hoogendijk WJ, Stam FC, et al.1994. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60(4): 436-44.
Rivier C, Shen GH.1994. In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocin. J Neurosci 14(4):1985-93.
Schulz E, Gori T, Munzel T.2011. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 34(6): 665-73.
Sebai H, Gadacha W, Sani M, et al.2009. Protective effect of resveratrol against lipopolysaccharide-induced oxidative stress in rat brain. Brain Inj 23(13-14): 1089-94.
Stern JE.2004. Nitric oxide and homeostatic control:an intercellular signalling molecule contributing to autonomic and neuroendocrine integration? Prog Biophys Mol Biol 84(2-3):197-215.
Stuehr DJ.1999. Mammalian nitric oxide synthases. Biochim Biophys Acta 1411(2-3): 217-30.
Willner P.1997. Validity, reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation. Psychopharmacology (Berl) 134(4): 319-29.
Willner P.2005. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52(2):90-110.
Wood J, Garthwaite J.1994. Models of the diffusional spread of nitric oxide: implications for neural nitric oxide signalling and its pharmacological properties. Neuropharmacology 33(11):1235-44.
Xing G, Chavko M, Zhang LX, et al.2002. Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophr Res 58(1):21-30.
Yamano Y, Yoshioka M, Toda Y, et al.2004. Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus. J Vet Med Sci 66(11):1323-7.
Yanik M, Vural H, Tutkun H, et al.2004. The role of the arginine-nitric oxide pathway in the pathogenesis of bipolar affective disorder. Eur Arch Psychiatry Clin Neurosci 254(1):43-7.
Zhou QG, Hu Y, Hua Y, et al.2007. Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis. J Neurochem 103(5):1843-54.
Zhou QG, Zhu LJ, Chen C, et al.2011. Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor. J Neurosci 31(21):7579-90.
Bao AM, Hestiantoro A, Van Someren EJ, et al.2005. Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in mood disorders. Brain 128(Pt 6): 1301-13.
Bao AM, Swaab DF.2007. Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic paraventricular nucleus and the role of sex hormones. Neuroendocrinology 85(1): 27-36.
Bernstein HG, Heinemann A, Krell D, et al.2002. Further immunohistochemical evidence for impaired NO signaling in the hypothalamus of depressed patients. Ann N Y Acad Sci 973:91-3.
Bernstein HG, Jirikowski GF, Heinemann A, et al.2000. Low and infrequent expression of nitric oxide synthase/NADPH-diaphorase in neurons of the human supraoptic nucleus:a histochemical study. J Chem Neuroanat 20(2):177-83.
Bernstein HG, Stanarius A, Baumann B, et al.1998. Nitric oxide synthase-containing neurons in the human hypothalamus:reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience 83(3):867-75.
Bhagwagar Z, Wylezinska M, Jezzard P, et al.2008. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 11(2):255-60.
Blum-Degen D, Heinemann T, Lan J, et al.1999. Characterization and regional distribution of nitric oxide synthase in the human brain during normal ageing. Brain Res 834(1-2):128-35.
Bossers K, Meerhoff G, Balesar R, et al.2009. Analysis of gene expression in Parkinson's disease:possible involvement of neurotrophic support and ax on guidance in dopaminergic cell death. Brain Pathol 19(1):91-107.
Casamenti F, Prosperi C, Scali C, et al.1999. Interleukin-lbeta activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer's disease. Neuroscience 91(3): 831-42.
Chapleau MW, Abboud FM.1994. Modulation of baroreceptor activity by ionic and paracrine mechanisms:an overview. Braz J Med Biol Res 27(4):1001-15.
Corasaniti MT, Paoletti AM, Palma E, et al.1995. Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat. Funct Neurol 10(3):151-5.
Cotter D, Mackay D, Landau S, et al.2001. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 58(6):545-53.
Drevets WC, Price JL, Furey ML.2008a. Brain structural and functional abnormalities in mood disorders:implications for neurocircuitry models of depression. Brain Struct Funct 213(1-2):93-118.
Drevets WC, Price JL, Simpson JR, Jr., et al.1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386(6627):824-7.
Drevets WC, Savitz J, Trimble M.2008b. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr 13(8):663-81.
Edwards FA, Konnerth A, Sakmann B, et al.1989. A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system. Pflugers Arch 414(5):600-12.
Egberongbe YI, Gentleman SM, Falkai P, et al.1994, The distribution of nitric oxide synthase immunoreactivity in the human brain. Neuroscience 59(3):561-78.
Eslinger PJ, Damasio AR.1985. Severe disturbance of higher cognition after bilateral frontal lobe ablation:patient EVR. Neurology 35(12):1731-41.
Ewald H, Degn B, Mors O, et al.1998. Significant linkage between bipolar affective disorder and chromosome 12q24. Psychiatr Genet 8(3):131-40.
Fallin MD, Lasseter VK, Avramopoulos D, et al.2005. Bipolar I disorder and schizophrenia:a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 77(6): 918-36.
Fitzgerald PB, Daskalakis ZJ.2011. A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. Brain Stimul.
Fleige S, Pfaffl MW.2006. RNA integrity and the effect on the real-time qRT-PCR performance. Mol Aspects Med 27(2-3):126-39.
Fronczek R, Overeem S, Lee SY, et al.2007. Hypocretin (orexin) loss in Parkinson's disease. Brain 130(Pt 6):1577-85.
Galecki P, Maes M, Florkowski A, et al.2011. Association between inducible and neuronal nitric oxide synthase polymorphisms and recurrent depressive disorder. J Affect Disord 129(1-3):175-82.
Gao SF, Bao AM.2011. Corticotropin-releasing hormone, glutamate, and gamma-aminobutyric acid in depression. Neuroscientist 17(1):124-44.
Gingerich S, Krukoff TL.2008. Activation of ERbeta increases levels of phosphorylated nNOS and NO production through a Src/P13K/Akt-dependent pathway in hypothalamic neurons. Neuropharmacology 55(5):878-85.
Green LC, Wagner DA, Glogowski J, et al.1982. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126(1):131-8.
Griffith OW, Stuehr DJ.1995. Nitric oxide synthases:properties and catalytic mechanism. Annu Rev Physiol 57:707-36.
Hasler G, van der Veen JW, Tumonis T, et al.2007. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64(2):193-200.
Hosaka N, Kimura S, Yamazaki A, et al.2008. Significant correlation between cerebrospinal fluid nitric oxide concentrations and neurologic prognosis in incomplete cervical cord injury. Eur Spine J 17(2):281-6.
Hyman BT, Marzloff K, Wenniger JJ, et al.1992. Relative sparing of nitric oxide synthase-containing neurons in the hippocampal formation in Alzheimer's disease. Ann Neurol 32(6):818-20.
Jhanwar VG, Bishnoi RJ, Jhanwar MR.2011. Utility of repetitive transcranial stimulation as an augmenting treatment method in treatment-resistant depression. Indian J Psychol Med 33(1):92-6.
Jopek R, Kata M, Nowak G.1999. The activity of rat brain nitric oxide synthase following chronic antidepressant treatment. Acta Pol Pharm 56(4):307-10.
Kamphuis W, Schneemann A, van Beek LM, et al.2001. Prostanoid receptor gene expression profile in human trabecular meshwork: a quantitative real-time PCR approach. Invest Ophthalmol Vis Sci 42(13):3209-15.
Kang YM, He RL, Yang LM, et al.2009. Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res 83(4):737-46.
Karolewicz B, Szebeni K, Stockmeier CA, et al.2004. Low nNOS protein in the locus coeruleus in major depression. J Neurochem 91(5):1057-66.
Koenigs M, Grafman J.2009. The functional neuroanatomy of depression:distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav Brain Res 201(2): 239-43.
McGuffin P, Knight J, Breen G, et al.2005. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum Mol Genet 14(22): 3337-45.
Miller KJ, Hoffman BJ.1994. Adenosine A3 receptors regulate serotonin transport via nitric oxide and cGMP. J Biol Chem 269(44):27351-6.
Milstien S, Sakai N, Brew BJ, et al.1994. Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J Neurochem 63(3):1178-80.
Morissette J, Villeneuve A, Bordeleau L, et al.1999. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in quebec points to a locus of major effect on chromosome 12q23-q24. Am J Med Genet 88(5):567-87.
Mufson EJ, Brandabur MM.1994. Sparing of NADPH-diaphorase striatal neurons in Parkinson's and Alzheimer's diseases. Neuroreport 5(6):705-8.
Narushima K, Kosier JT, Robinson RG.2003. A reappraisal of poststroke depression, intra-and inter-hemispheric lesion location using meta-analysis. J Neuropsychiatry Clin Neurosci 15(4):422-30.
Oliveira RM, Guimaraes FS, Deakin JF.2008. Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. Braz J Med Biol Res 41(4):333-41.
Prast H, Philippu A.2001. Nitric oxide as modulator of neuronal function. Prog Neurobiol 64(1):51-68.
Quide Y, Witteveen AB, El-Hage W, et al.2011. Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder:A systematic review. Neurosci Biobehav Rev.
Racagni G, Brunello N.1999. Physiology to functionality:the brain and neurotransmitter activity. Int Clin Psychopharmacol 14 Suppl 1:S3-7.
Rajkowska G, Halaris A, Selemon LD.2001. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 49(9):741-52.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al.1999. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45(9):1085-98.
Reif A, Strobel A, Jacob CP, et al.2006. A NOS-Ⅲ haplotype that includes functional polymorphisms is associated with bipolar disorder. Int J Neuropsychopharmacol 9(1):13-20.
Rejdak K, Petzold A, Stelmasiak Z, et al.2008. Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis. Mult Scler 14(1):59-66.
Segovia G, Porras A, Mora F.1994. Effects of a nitric oxide donor on glutamate and GABA release in striatum and hippocampus of the conscious rat. Neuroreport 5(15):1937-40.
Shan L, Bossers K, Luchetti S, et al.2011. Alterations in the histaminergic system in the substantia nigra and striatum of Parkinson's patients:a postmortem study. Neurobiol Aging.
Silberberg G, Ben-Shachar D, Navon R.2010. Genetic analysis of nitric oxide synthase 1 variants in schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 153B(7):1318-28.
Swaab DF, Fliers E, Hoogendijk WJ, et al.2000. Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression. Prog Brain Res 126: 369-96.
Tohgi H, Abe T, Yamazaki K, et al.1998. The cerebrospinal fluid oxidized NO metabolites, nitrite and nitrate, in Alzheimer's disease and vascular dementia of Binswanger type and multiple small infarct type. J Neural Transm 105(10-12): 1283-91.
Vandesompele J, De Preter K, Pattyn F, et al.2002. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034.
Wang SS, Kamphuis W, Huitinga I, et al.2008. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR:the presence of multiple receptor imbalances. Mol Psychiatry 13(8):786-99,741.
Xing G, Chavko M, Zhang LX, et al.2002. Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophr Res 58(1):21-30.
Yan XX, Jen LS, Garey LJ.1996. NADPH-diaphorase-positive neurons in primate cerebral cortex colocalize with GABA and calcium-binding proteins. Cereb Cortex 6(3):524-9.
Yao JK, Leonard S, Reddy RD.2004. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr Bull 30(4):923-34.
Yew DT, Wong HW, Li WP, et al.1999. Nitric oxide synthase neurons in different areas of normal aged and Alzheimer's brains. Neuroscience 89(3):675-86.
Yu YW, Chen TJ, Wang YC, et al.2003. Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response. Neuropsychobiology 47(3):137-40.
Altamura C, Maes M, Dai J, et al.1995. Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur Neuropsychopharmacol 5 Suppl:71-5.
Altamura CA, Mauri MC, Ferrara A, et al.1993. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150(11):1731-3.
Bao AM, Fischer DF, Wu YH, et al.2006. A direct androgenic involvement in the expression of human corticotropin-releasing hormone. Mol Psychiatry 11(6): 567-76.
Bao AM, Meynen G, Swaab DF.2008. The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 57(2): 531-53.
Beneyto M, Kristiansen LV, Oni-Orisan A, et al.2007. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32(9):1888-902.
Castillo M, Kwock L, Courvoisie H, et al.2000. Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations. AJNR Am J Neuroradiol 21(5):832-8.
Charney DS.1998. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 59 Suppl 14:11-4.
Choudary PV, Molnar M, Evans SJ, et al.2005. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102(43):15653-8.
Ducottet C, Griebel G, Belzung C.2003. Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice. Prog Neuropsychopharmacol Biol Psychiatry 27(4):625-31.
Frye MA, Tsai GE, Huggins T, et al.2007a. Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol Psychiatry 61(2):162-6.
Frye MA, Watzl J, Banakar S, et al.2007b. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 32(12):2490-9.
Gerner RH, Fairbanks L, Anderson GM, et al.1984. CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. Am J Psychiatry 141(12):1533-40.
Gold BI, Bowers MB, Jr., Roth RH, et al.1980. GABA levels in CSF of patients with psychiatric disorders. Am J Psychiatry 137(3):362-4.
Heckers S, Stone D, Walsh J, et al.2002. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry 59(6):521-9.
Herman JP, Mueller NK, Figueiredo H.2004. Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci 1018: 35-45.
Heuser I, Bissette G, Dettling M, et al.1998. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress Anxiety 8(2):71-9.
Hoekstra R, Fekkes D, Loonen AJ, et al.2006. Bipolar mania and plasma amino acids: increased levels of glycine. Eur Neuropsychopharmacol 16(1):71-7.
Holden C.2000. Mental health. Global survey examines impact of depression. Science 288(5463):39-40.
Kasa K, Otsuki S, Yamamoto M, et al.1982. Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. Biol Psychiatry 17(8): 877-83.
McCullumsmith RE, Kristiansen LV, Beneyto M, et al.2007. Decreased NR1, NR2A, and SAP 102 transcript expression in the hippocampus in bipolar disorder. Brain Res 1127(1):108-18.
McCullumsmith RE, Meador-Woodruff JH.2002. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26(3):368-75.
Michael N, Erfurth A, Ohrmann P, et al.2003. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol Med 33(7): 1277-84.
Mitani H, Shirayama Y, Yamada T, et al.2006. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1155-8.
Nemeroff CB.1996. The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1(4):336-42.
Nemeroff CB.1998. The neurobiology of depression. Sci Am 278(6):42-9.
Overstreet DH, Griebel G.2004. Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression. Eur J Pharmacol 497(1):49-53.
Petty F.1995. GABA and mood disorders:a brief review and hypothesis. J Affect Disord 34(4):275-81.
Petty F, Kramer G. 1992. Stability of plasma gamma-aminobutyric acid with time in healthy controls. Biol Psychiatry 31(7):743-5.
Petty F, Kramer GL, Fulton M, et al.1995. Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression. Biol Psychiatry 37(11): 806-10.
Rosenberg DR, Macmaster FP, Mirza Y, et al.2005. Reduced anterior cingulate glutamate in pediatric major depression: a magnetic resonance spectroscopy study. Biol Psychiatry 58(9):700-4.
Sanacora G, Gueorguieva R, Epperson CN, et al.2004. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61(7):705-13.
Sanacora G, Mason GF, Rothman DL, et al.1999. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56(11):1043-7.
Sanacora G, Mason GF, Rothman DL, et al.2003. Increased cortical GAB A concentrations in depressed patients receiving ECT. Am J Psychiatry 160(3): 577-9.
Sanacora G, Mason GF, Rothman DL, et al.2002. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4):663-5.
Sanacora G, Saricicek A.2007. GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS Neurol Disord Drug Targets 6(2):127-40.
Stryjer R, Strous RD, Shaked G, et al.2003. Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol 18(2): 93-6.
Swaab DF, Bao AM, Lucassen PJ.2005. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4(2):141-94.
Taylor M, Murphy SE, Selvaraj S, et al.2008. Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectroscopy. J Psychopharmacol 22(5):473-6.
Torrey EF, Barci BM, Webster MJ, et al.2005. Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. Biol Psychiatry 57(3):252-60.
Verkuyl JM, Hemby SE, Joels M.2004. Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. Eur J Neurosci 20(6):1665-73.
Woo TU, Walsh JP, Benes FM.2004. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61(7):649-57.
Zarate CA, Jr., Payne JL, Quiroz J, et al.2004. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161(1):171-4.
Zarate CA, Jr., Singh JB, Carlson PJ, et al.2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856-64.